1. Field of the Invention
The present invention relates to the use of bacteriophages to treat infectious diseases whereby the host-specific, wide host-range bacteriophages are present, in purified form, in non-toxic sufficiently virulent compositions that can be administered to patients or mammals in need thereof. The bacteriophages are useful in treating infections due to bacterial microorganisms by killing a sufficient quantity of the bacterial microorganisms or by rendering the bacterial microorganisms more susceptible to other chemotherapeutic antibiotics.
2. Description of Related Art
Bacteriophages (phages) are a heterogeneous group of viruses that infect bacteria that were first discovered in the early part of the 20th century. d'Herelle, F., The bacteriophage. Its role in immunity, translated by Smith, G. H., Williams & Wilkins Co., Baltimore (1922). Bacteriophages presently are widely used in scientific research, such as in molecular biology (e.g. as genetic vectors) and in medical diagnostics (e.g. phage typing of bacteria). Insofar as phages naturally infect and kill bacteria, it traditionally was suggested that they could be utilized in medical therapeutics, because bacteria are a major cause of disease.
Indeed, potential therapeutic uses of phage in experimental systems have been reported extensively in the literature (d'Herelle, F., The bacteriophage and its clinical applications, Charles C. Thomas, Baltimore (1930)). None of these potential experimental therapeutic uses has resulted in the formulation of an efficacious bacteriophage preparation, i.e., one that is sufficiently virulent, non-toxic, host-specific, and with wide enough host range to be of practical use. The notion of phage therapeutics has not resulted in practical usage because: (i) efficacy has been marginal or non-existent; (ii) toxic side effects of phage therapy have been unacceptable; (iii) better alternatives such as conventional chemical antibiotics have existed; (iv) conventional bacteriophage preparations are contaminated with debris from bacterial lysis which typically contain toxins; (v) an antibody response to the bacteria can be initiated upon introduction of the phage; and (v) phage preparations do not arrive at the target site because they are removed too fast from the body once injected or ingested. Thus, with respect to phage therapeutics in the use of ameliorating or treating specific animal infections, there is no currently known practical workable concept or method. Ostensibly, therefore, there is practically no known specifically useful phage therapeutic or composition of matter containing a phage therapeutic. In addition to the above general limitations, there also have been little or no reported advantages for the use of phage therapeutics such as, for example, (i) useful innovations for administration of phage therapy, (ii) adjunctive therapeutic use of phage therapy with other antibiotherapeutics, or (iii) for use in the context of microorganism resistance to conventional therapies.
Despite the recognized value and importance of new antimicrobial therapies, the potential of phage therapy has not been accomplished in any practical sense that is used in modern therapeutics, nor have methods, compositions, or other uses been defined for nontoxic and efficacious therapies of this type with practical and effective delivery. Phage preparations known in the art and available today are not known to be effective in treating mammalian bacterial infections (AMERICAN TYPE CULTURE COLLECTION CATALOGUE OF BACTERIA AND BACTERIOPHAGES, (ATCC) 18th Edition, pages 402–411 (1992). It is believed that conventional, or wild-type phage preparations are: (i) incapable of surviving for sufficient periods of time in vivo; (ii) impure in that they contain various strains of bacteriophage including mutated phage and the like which are not virulent to the respective bacterial microorganism, as well as a host of bacterial impurities; (iii) toxic; and (iv) not host-specific in that they do not tend to migrate primarily to the bacterial infections.
Recent approaches have attempted to make use of phage therapeutics by utilizing bacteriophages that are selected using a specific serial passage method to produce longer circulating bacteriophages. Specific bacteriophages have been developed to Escherichia coli and Salmonella typhimurium by first isolating bacteriophages and mutants thereof that are specific to these bacterial microorganisms, and then purifying these bacteriophages and selecting the strains that are capable of avoiding entrapment in the reticuloendothelial system of the animal by consecutive cycles of injecting the phage into the animal, isolating the phage in the blood of the animal and regrowth of the phage in the bacteria. The use of this serial passage method in ascertaining efficacious bacteriophage, however, is extremely costly and time consuming to develop and it is of known usefulness in the majority of infections. Furthermore, a longer circulating bacteriophage is not precluded from being less virulent and therefore ineffective as a potential or theoretical treatment. This method of developing bacteriophage preparations therefore is undesirable, and the selection criteria utilized likely will not yield a virulent, non-toxic host-specific bacteriophage preparation.
One of the primary reasons why bacteriophages have not been utilized to treat bacterial infections and bacterial microorganisms is due to the widespread use of antibiotics. Numerous strains of bacteria and microorganisms have evolved, however, which are resistant to conventional antibiotics. There exists a need, therefore, to develop methods of treating bacterial infections that are resistant to conventional antibiotics or to develop a method that can complement the antibiotherapy.
In addition, there exists a need to develop new and useful phage therapeutics which can be used to treat infectious disorders caused by bacterial microorganisms. There also exists a need to develop compositions including phage therapeutics in pharmaceutically acceptable vehicles that can be administered to subjects infected with bacterial microorganisms. There is an additional need to develop a method that is capable of delineating useful phage therapeutics that is efficient and economically feasible. There also exists a need to develop new and useful phage therapeutics that are useful in combination with antibiotics to treat infectious disorders caused by bacterial microorganism infection. Finally, there exists a need to develop a bacteriophage preparation that is host-specific, virulent and non-toxic thereby rendering it useful in treating bacterial infections.
Examination of past failures with phage therapeutic attempts and modern approaches to these failures, have now revealed that phages used for antibacterial therapies in certain specific situations are highly important which make this new type of treatment very attractive and useful. The bacteriophage preparations, however, must be selected so that virulent, non-toxic, host-specific preparations are formulated. Thus, there is a need to develop host-specific, non-toxic and virulent bacteriophage preparations that can be used to effectively treat bacterial infections in a mammal.